Angiotensin-converting enzyme enhances the oxidative response and bactericidal activity of neutrophils

Zakir Khan, Xiao Z. Shen, Ellen A. Bernstein, Jorge F. Giani, Masahiro Eriguchi, Tuantuan V. Zhao, Romer A. Gonzalez-Villalobos, Sebastien Fuchs, George Y. Liu, Kenneth E. Bernstein

Research output: Contribution to journalArticle

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Abstract

Angiotensin-converting enzyme (ACE) inhibitors are widely used to reduce blood pressure. Here, we examined if an ACE is important for the antibacterial effectiveness of neutrophils. ACE knockout mice or mice treated with an ACE inhibitor were more susceptible to bacterial infection by methicillin-resistant Staphylococcus aureus (MRSA). In contrast, mice overexpressing ACE in neutrophils (NeuACE mice) have increased resistance to MRSA and better in vitro killing of MRSA, Pseudomonas aeruginosa, and Klebsiella pneumoniae. ACE overexpression increased neutrophil production of reactive oxygen species (ROS) following MRSA challenge, an effect independent of the angiotensin II AT1 receptor. Specifically, as compared with wild-type (WT) mice, there was a marked increase of superoxide generation (>twofold, P < .0005) in NeuACE neutrophils following infection, whereas ACE knockout neutrophils decreased superoxide production. Analysis of membrane p47-phox and p67-phox indicates that ACE increases reduced NAD phosphate oxidase activity but does not increase expression of these subunits. Increased ROS generation mediates the enhanced bacterial resistance of NeuACE mice because the enhanced resistance is lost with DPI (an inhibitor of ROS production by flavoenzymes) inhibition. NeuACE granulocytes also have increased neutrophil extracellular trap formation and interleukin-1b release in response to MRSA. In a mouse model of chemotherapy-induced neutrophil depletion, transfusion of ACE-overexpressing neutrophils was superior to WT neutrophils in treating MRSA infection. These data indicate a previously unknown function of ACE in neutrophil antibacterial defenses and suggest caution in the treatment of certain individuals with ACE inhibitors. ACE overexpression in neutrophils may be useful in boosting the immune response to antibiotic-resistant bacterial infection.

Original languageEnglish
Pages (from-to)328-339
Number of pages12
JournalBlood
Volume130
Issue number3
DOIs
Publication statusPublished - Jul 20 2017

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Peptidyl-Dipeptidase A
Neutrophils
Methicillin
Methicillin-Resistant Staphylococcus aureus
Angiotensin-Converting Enzyme Inhibitors
Reactive Oxygen Species
Superoxides
Bacterial Infections
Chemotherapy
Interleukins
Angiotensin Type 1 Receptor
Blood pressure
Angiotensin Receptors
Klebsiella pneumoniae
Angiotensin II
NAD
Infection
Granulocytes
Knockout Mice
Pseudomonas aeruginosa

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Khan, Z., Shen, X. Z., Bernstein, E. A., Giani, J. F., Eriguchi, M., Zhao, T. V., ... Bernstein, K. E. (2017). Angiotensin-converting enzyme enhances the oxidative response and bactericidal activity of neutrophils. Blood, 130(3), 328-339. https://doi.org/10.1182/blood-2016-11-752006

Angiotensin-converting enzyme enhances the oxidative response and bactericidal activity of neutrophils. / Khan, Zakir; Shen, Xiao Z.; Bernstein, Ellen A.; Giani, Jorge F.; Eriguchi, Masahiro; Zhao, Tuantuan V.; Gonzalez-Villalobos, Romer A.; Fuchs, Sebastien; Liu, George Y.; Bernstein, Kenneth E.

In: Blood, Vol. 130, No. 3, 20.07.2017, p. 328-339.

Research output: Contribution to journalArticle

Khan, Z, Shen, XZ, Bernstein, EA, Giani, JF, Eriguchi, M, Zhao, TV, Gonzalez-Villalobos, RA, Fuchs, S, Liu, GY & Bernstein, KE 2017, 'Angiotensin-converting enzyme enhances the oxidative response and bactericidal activity of neutrophils', Blood, vol. 130, no. 3, pp. 328-339. https://doi.org/10.1182/blood-2016-11-752006
Khan, Zakir ; Shen, Xiao Z. ; Bernstein, Ellen A. ; Giani, Jorge F. ; Eriguchi, Masahiro ; Zhao, Tuantuan V. ; Gonzalez-Villalobos, Romer A. ; Fuchs, Sebastien ; Liu, George Y. ; Bernstein, Kenneth E. / Angiotensin-converting enzyme enhances the oxidative response and bactericidal activity of neutrophils. In: Blood. 2017 ; Vol. 130, No. 3. pp. 328-339.
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